The capacity of embryonic stem cells (ESCs) to give rise to all types of somatic cells together with their ability to grow indefinitely in culture underscores their potential for in vivo therapeutic applications. However, many challenges exist, for example, ES cells are not genetically identical to the organism from which they are harvested, and thus rejection and immunogenicity are two concerns that potentially limit their future use in clinical transplantation. In addition, ethical concerns have been raised regarding the derivation of human ES cells from human embryos. For these reasons considerable effort has been invested in attempting to derive pluripotent stem cells from post-natal tissue that may be employed for isogenic or autologous transplantation. However, the generation of patient-specific autologous ESCs is technically challenging and further complicated by ethical concerns, significantly limiting their potential for clinical transplantation. The reprogramming of fibroblasts to an ESC-like state, pioneered by Yamanaka and colleagues, has advanced stem cell research (Takahashi and Yamanaka, 2006, Cell 126:663-676) by circumventing these obstacles. These so called ‘induced Pluripotent Stem (iPS) cells’ derived from mouse or human fibroblasts have demonstrated that an entire organism can be derived from readily accessible post-natal somatic cells. iPS cells provide a powerful in vitro model system for the study of the molecular mechanisms of reprogramming and have been successfully employed in proof-of-principle cell-based therapies in mouse models of disease. However, to date the derivation of iPS cells has required multiple individual viral vectors to deliver the constellation of transcription factors (typically OCT4, SOX2, KLF4, and c-MYC) required to induce reprogramming. The application of sufficient quantities of each virus needed to deliver four factors simultaneously to each target cell results in high numbers of genomic integrations in successfully reprogrammed progeny. This presence of multiple viral integrations across the genome makes their genetic elimination to produce safer iPS cells very difficult. Moreover, many cells will receive only one, two or three factors, making it difficult to study the biochemistry of reprogramming on a homogeneous population of cells. Hence there is a need for improved methods that provide consistent delivery of reprogramming transcription factors and with minimal or no viral integrations across the genome to produce safer iPS cells.